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Access Type

WSU Access

Date of Award

January 2015

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Molecular Biology and Genetics

First Advisor

Alexander Gow

Abstract

In the current study, we have generated mutant mice that lack Claudin 11 (Cldn11) tight junctions in CNS myelin sheaths. In myelin sheaths, Cldn11 forms tight junctions located along the outer and inner edges of the membrane spiral, preventing ions and small molecules from entering the intramyelinic space. The function of Cldn11 tight junctions is to improve the passive properties of the myelin membrane, by increasing membrane resistance and reducing capacitance, thereby improving the speed of saltatory conduction. In the absence of Cldn11, conduction velocity is slowed, most dramatically in small diameter myelinated fibers, somewhat analogous to reducing myelin thickness. Notably, the absence of Cldn11 is without degenerative myelin pathology, enabling direct study on the impact of dysfunctional myelin on neural processing.

Undoubtedly, slowed conduction velocity along myelinated axons increases temporal dispersion and, consequently, degrades information transfer between neural circuits. Herein, this dissertation work explores the impact of dysfunctional myelin on neural processing in the conserved integration circuit of the auditory brainstem. We find that dysfunctional myelin alters neural processing, generating an inability to lateralize sound sources on the azimuth plane. Extrapolating this information to higher order circuitry within the cortex, we find that dysfunctional myelin generates a disconnection between brain regions, manifesting in behavioral abnormalities and alteration in neurotransmitter levels.

Together, these data demonstrate that non-degenerative changes in myelin membrane passive properties can lead to neurochemistry changes that perturb behavior/perception. Second, they have important implications for the etiology of behavioral disorders in general, and more specifically for the behavioral components of hypomyelinating and demyelinating diseases like multiple sclerosis.

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